Doped membranes

ABSTRACT

Synthetic membranes for the removal, isolation or purification of substances from a liquid. The membranes include at least one hydrophobic polymer and at least one hydrophilic polymer. 5-40 wt.-% of particles having an average particles size of between 0.1 and 15 μm are entrapped. The membrane has a wall thickness of below 150 μm. Methods for preparing the membranes in various geometries, and use of the membranes for the adsorption, isolation and/or purification of substances from a liquid are explored.

TECHNICAL FIELD

The present disclosure relates to synthetic membranes for the removal,isolation or purification of substances from a liquid, comprising atleast one hydrophobic and at least one hydrophilic polymer, wherein 5-40wt.-% of particles having an average particles size of between 0.1 and15 μm are entrapped in the membrane and wherein the membrane has a wallthickness of below 150 μm. Further disclosed are methods for preparingsuch membranes in various geometries and their use for the adsorption,isolation and/or purification of substances from a liquid.

DESCRIPTION OF THE RELATED ART

Synthetic membranes with entrapped particles or ionic charges have beendescribed before in the prior art.

WO 2004/003268 A1 describes the basic approach for the preparation ofporous polymeric fibers comprising a broad variety of functionalized oractive particles, wherein a solution of one or more polymers is mixedwith particulate material and wherein the mixture is extruded into afiber by a two-step inversion process. WO 2004/003268 A1 also describesthat porous polystyrene or styrene-divinylbenzene type particles, eitherunmodified or modified with sulphonic acids or quaternary amines maypossibly be used as particulate material. However, WO 2004/003268 A1does not teach how stable porous or non-porous membranes can be preparedwhich contain ion exchange particles in amount of about 5-40 wt.-%,wherein the particles have a very small average diameter. Whereas thereference teaches that it may be beneficial to have small particles,below 15 μm, entrapped in the membrane, it is taught that particle loadshould be higher. In the examples, all membranes have a particle load of50 wt.-% or higher. Such high load of particles of above 50% wt.-% issaid to be preferred for improving the accessibility of the particlesand for obtaining a stable membrane structure under avoidance of theformation of macrovoids (Example 6 and FIGS. 7 and 8).

It is a problem, when preparing membranes with entrapped particles, toobtain stable membranes, especially hollow fiber membranes. In theprocesses as described in the prior art, hollow fiber membranes tend toget unstable due to the formation of macrovoids and varying wallthicknesses. The spinning is generally difficult and the process isoften interrupted because the fibers get torn at the spinning nozzleduring spinning. Therefore, fibers as can be seen in the prior art aregenerally solid fibers or hollow fibers with higher wall thickness ofabout 250 μm.

The applicants have found that it is possible to prepare membranes,especially also hollow fiber membranes with a wall thickness of below150 μm with a considerably lower particle load of below 40 wt.-%,wherein both the physical stability and efficiency of the membrane isimproved in comparison to membranes with higher particle load and/orparticles with an average diameter of above about 20 μm. This isachieved by an improved process for preparing a membrane with entrappedparticles, comprising an improved generation and maintenance ofparticles with an average size of about 0.1 to 15 μm and an improvedprocess for generating a spinning solution comprising said particles,resulting in a stable spinning process and stable membranes.

WO 2006/019293 A1 relates to hollow or solid fiber membranes havingmultiple porous layers which are concentrically arranged, and wherein atleast one of the layers comprises functionalized or active particles asdescribed in WO 2004/003268 A1 above. The layer containing high loads ofparticles can be either the outer or the inner layer, wherein thefunction of the other layer, without particles, is to provide mechanicalstability to the fiber. As described before, WO 2006/019293 A1 does notdisclose ways to obtain stable membranes with low particle load whichcan be prepared as hollow fiber membranes without adjacent stabilizinglayers.

EP 1 038 570 A1 describes the preparation of positively chargedmembranes including a sulfone polymer and PVP and a cationicimidazolinium compound. However, the cationic material is not present inthe membrane in form of particulate material.

The applicants have found methods to produce and provide mechanicallystable membranes which can be produced as solid, hollow fiber or flatsheet membranes and which have specifically and stably entrapped thereinparticles such as ion exchange particles in an amount of preferably 5-40wt.-%, wherein the average particle size is below 15 μm and generally inthe range of between 0.1 and 10 μm, especially in the range of from 0.1to 1.0 μm. The applicants further found that based on the process forpreparing the new membranes and the resulting nature of such membranesof the invention, the comparatively low particle load of the membrane ishighly effective for adsorbing, isolating and/or removing certaincompounds from liquids, such as, for example, nucleic acids, toxins,such as endotoxins, unconjugated bilirubin, diazepam, and alsoproblematic endogenous substances such as cytokines or the like.

SUMMARY

It is an object of the present invention to provide more efficient andmechanically more stable synthetic membranes which can be used for theadsorption, purification or isolation of compounds from a liquid. Oneobject of the present invention was to provide membranes in a hollowfiber geometry with a wall thickness which is smaller compared to theprior art, thus providing better accessibility and higher efficiency ofthe membrane when used.

It was found, surprisingly, that very efficient and mechanically stabledoped membranes may be prepared wherein the membrane has entrappedtherein particles which are very small. The membrane is furthercharacterized by a low particle load. At the same time the wallthickness of the membranes is considerably lower than in the art. It wasfound that such membranes should have entrapped therein particles withan average size (diameter) of between 0.1 and 1.0 μm, and notessentially more than 15 μm, even though relatively good membranes canbe obtained with 20 μm particles as well. Further, a particle load of upto 50%, generally of between 5 and 40 wt.-%, may be achieved.

Accordingly, it was a further aspect of the present invention to devisea process for preparing such membranes. It was one object of theinvention to provide a process which allows the preparation of particleswith an average size of well below 15 μm, wherein the new process shouldalso prevent the agglomeration of the particles once they are added tothe spinning solution and during the spinning process.

It was also an object of the present invention to provide a dopedmembrane such as a hollow fiber membrane with increased effectiveness ofthe membrane when used in methods for removing a specific targetsubstance from a liquid.

The membranes with such small size particles and low particle load showan improved activity or efficiency with regard to the removal oradsorption of the respective target substances from a liquid compared tomembranes having a higher particle load and/or larger particles andhigher wall thickness.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a SEM of a microporous hollow fiber membrane according toExamples 2.1 and 3 which is based on polyethersulfone and PVP andwherein the particles were grinded in the presence of NMP and water.FIG. 1A shows the complete cross-section (200×) of the membrane, whereasFIG. 1B shows the magnification (1000×) of the cross-section of FIG. 1A.The entrapped basic anion exchange particles (cholestyraminee (DOWEX™1×2-Cl)) in which quaternary ammonium groups are attached to astyrene/divinylbenzene copolymer chain are not visible in the membraneat a magnifications of 200. It is possible, at a magnification of 1000(see also FIG. 2A), to discern tiny particles which are completelyentrapped in the membrane. It can be seen that the particles' averagesize is well below about 5 μm (see also FIG. 2).

FIG. 2 shows a SEM of the inner and outer surface of the microporoushollow fiber membrane. The SEM have been taken from the same membrane asthe SEM of FIG. 1. FIG. 2A shows the inner or lumen side of the membraneat a magnification of 2.500. FIG. 2B shows the outer surface of thehollow fiber membrane at the same magnification.

FIG. 3 shows a SEM of the cross-section of a hollow fiber membrane witha magnification of 200 (FIG. 3A). FIG. 3B shows the wall of the membraneat a magnification of 1000. The membrane was prepared according toComparative Examples 2, 2.2 and 3 (Batch C), wherein the anion exchangeparticles (DOWEX™ 1×2-Cl) were grinded in NMP in the absence of water toabout the same initial size as in Example 2.1 (see also FIGS. 1 and 2).As can be seen, the particles as present in the final membrane arelarger as in FIG. 1, even though it should be noted that the SEM shows adry membrane wherein the particles have undergone some shrinking. Theyare present in distinct cavities within the membrane and eventuallybreak through the surface of the membrane, thus increasing the risk ofparticles being washed out into the adjacent liquid. Without wanting tobe limited to the theory, it is assumed that the cavities are formed bythe water which is taken up by the particles and serves as aprecipitating agent around said particles. During use of the membrane,the membrane will usually be contacted again with water or an aqueoussolution, which will lead to the renewed swelling of the particles. Theactual average diameter of the particles during use is thus larger thanthe average diameter displayed in the SEM.

FIG. 4 shows the average size (diameter in μm) of two exemplary batchesof cholestyramine particles after grinding in aqueous solution in thepresence of an organic solvent in a LabStar LS 1 LMZ machine with ZrO₂as agitator grinding medium and a temperature of 50° C. (see Ex. 1). Thedata are shown as provided by the Horiba LA950 for Windows Version 3.40software. The particles of FIG. 4A were obtained after 60 minutes ofgrinding; the particles of FIG. 4B were obtained after 120 minutes ofgrinding.

FIG. 5 shows the average size (diameter in μm) of another exemplarybatch of cholestyramine particles after 300 minutes of grinding in thepresence of an organic solvent (NMP) in a LabStar LS 1 LMZ machine withZrO₂ as agitator grinding medium and a temperature of 50° C. The dataare shown as provided by the Horiba LA950 for Windows Version 3.40software. The average diameter was about 8.0 μm.

FIG. 6 shows Lp and DNA retention capability of different membranes ofhollow fiber and flat sheet geometry. For comparative reasons, astandard ultrafiltration membrane without any added material was tested(see also Example 6). Also shown is a hollow fiber membrane withentrapped Amberlite® IRA-410 particles and a hollow fiber membrane withmodified PPE ion-exchanger additive (Example 7). A flat sheet membranewas also tested. It contained Luviquat® FC 370 (Example 5). DNAretention is improved in the presence of ion exchange material inmembranes which have been prepared according to the invention.

FIG. 7 shows a SEM of a comparative flat sheet membrane containingAmberlite® IRA-410 particles. The membrane was prepared according toExample 6 and is shown at a magnification of 2020. Larger particles areclearly visible in the membrane structure, as are ruptures on thesurface of the pores of the membrane.

FIG. 8 shows the results of DNA retention (adsorption) tests done withmini-modules prepared from Amberlite® IRA-410 containing membranesproduced according to Example 4. The Figure shows the feed DNA solutionand the DNA concentration in the filtrate for a standard membranewithout Amberlite®IRA-410 (Table Vb, Samples 10-13) and with differentconcentrations of Amberlite® IRA-410 (Table Vb, Samples 3-5 and 6-8,respectively). The presence of Amberlite® IRA-410 leads to a significantadsorption of the DNA, with a higher rate for membranes with a highercontent of Amberlite® IRA-410.

DETAILED DESCRIPTION

The present invention is directed to more efficient and mechanicallystable synthetic membranes which can be used for the adsorption,purification or isolation of compounds from a liquid, wherein themembranes have entrapped therein particles which can be chosen accordingto the needs of the adsorption, purification or isolation task.

The expression “doped membrane” as used herein refers to the inclusionof particles (which might also be referred to as “impurities”) into amembrane during its formation for the purpose of modulating itsproperties.

The expression “particles” as used herein, refers to solid or gel-likefragments of certain solid or gel-type materials, such as hydrophobicmaterials or ion exchange materials. The expression “gel” or “gel-type”as used herein, refers to materials or resins with no permanent porestructures. Said pores are generally considered to be small and, ingeneral, not greater than 30 Å, and are referred to as gelular pores ormolecular pores. The pore structures are determined by the distancebetween the polymer chains and cross-links which vary with the crosslinklevel of the polymer, the polarity of the solvent and the operatingconditions. The gel type resins are generally translucent. The fragmentsor particles may have different shapes, such as approximately sphericalshapes or irregular, edged shapes which may be stretched or cubical. Theparticles as discussed in the context of the present invention have anaverage size (diameter) of from 0.1 to about 100 μm.

The expression “ion exchange material” as used herein, refers aninsoluble polymeric matrix containing labile ions capable of exchangingwith ions in the surrounding medium. Generally, ion exchange resins aresupplied water wet in the form of approximately spherical beads having aparticle diameter between 0.30 and 1.2 mm. A given resin has acharacteristic water content associated with the functional groups andadhering to the outer surface of the resin particles. Notably, water wetion exchange resins shrink or swell when they change from one ionic formto another and they shrink when they are dried and/or are in contactwith non-polar solvents.

It is one aspect of the present invention that the membranes accordingto the invention can be provided in various geometries, covering flatsheet and solid fibers as well as hollow fibers. It is a specific aspectof the present invention that hollow fiber membranes can be preparedwhich have a wall thickness which is smaller compared to the prior art,thus providing better accessibility and higher efficiency of themembrane when used.

It is a problem, when preparing membranes with entrapped particlesaccording to the prior art to obtain stable membranes, especially hollowfiber membranes. In the processes as described in the prior art, hollowfiber membranes tend to get unstable due to the formation of macrovoidsand varying wall thicknesses. The spinning is generally difficult andthe process is often interrupted because the fibers get torn at thespinning nozzle during spinning. Therefore, fibers as can be seen in theprior art are generally solid fibers or hollow fibers with higher wallthickness of about 250 μm. Accordingly, in one aspect of the presentinvention, the membranes, either hollow fiber or flat sheet membranes,have a wall thickness of below 150 μm. According to a specific aspect ofthe present invention, the wall thickness is between 100 and 150 μm.

According to another aspect of the present invention, it is crucial forobtaining such membranes wherein both the physical stability of themembrane is improved in comparison to membranes of the prior art and thewall thickness is reduced, to prepare membranes with a lower particleload of below 40 wt.-%. According to a specific aspect of the presentinvention, the particle load should be in the range of between 5 wt.-%and 40 wt.-% relative to the total weight of the membrane. In yetanother aspect of the present invention, the particle load should be ina range of from 20 wt.-% and 35 wt.-% of the total weight of themembrane.

At the same time, it is important to closely control the average size ofthe particles and their behaviour in the spinning solution. Particlesize data, as used herein, refer to the particles in a wet state both assuch and when incorporated in a membrane. It was found that particleswith an average diameter of more than 15 or 20 μm are problematic forobtaining useful membranes. The same is true for smaller particles ofbelow said 15 to 20 μm, which may be as small as between 1 μm and 0.1 μmin diameter at the time of grinding, if the process of grinding andpreparing a spinning solution as well as the spinning itself are notcontrolled in a way that the particles stay apart from each other andwill not agglomerate immediately upon grinding and especially duringformation of the spinning solution and the spinning itself. Accordingly,it is one aspect of the present invention to provide a membrane whereinthe entrapped particles have an average diameter of below 20 μm,preferably below 15 μm. According to one aspect of the presentinvention, the entrapped particles should have an average diameter ofbelow 10 μm. According to one aspect of the present invention, theaverage diameter of the entrapped particles should be below 15 μm.According to another aspect of the present invention, the averagediameter of the entrapped particles should be in a range of from 0.1 μmto 10 μm.

The particles which can be entrapped in a membrane according to theinvention and the processes disclosed herein may be of various nature,such as also disclosed in the prior art (WO 2004/003268 A1, incorporatedherein by reference). According to one aspect of the present invention,the particles are ion exchange particles which are prepared from ionexchange material widely known in the art which is also commerciallyavailable. According to one specific aspect of the present invention,cation or anion exchange material can be used for preparing the dopedmembranes of the invention. According to another aspect of the presentinvention, the particles are hydrophobic particles chosen from the groupconsisting of activated carbon, carbon nanotubes, hydrophobic silica,styrenic polymers, polydivinylbenzene polymers andstyrene-divinylbenzene copolymers.

According to one aspect of the invention, basic anion exchange materialis used for preparing the doped membranes, which may be based onpolystyrene or styrene-divinylbenzene and which may be modified withsulphonic acids, polyamines or quaternary or tertiary amines. Accordingto one aspect of the invention, the particles are based on a copolymerof styrene and divinylbenzene carrying active groups such as quaternaryammonium groups, dimethylethanolamine groups, dimethylethanolbenzylammonium groups, benzyltrialkyl ammonium groups,benzyldimethyl(2-hydroxyethyl) ammonium and/or trimethylbenzyl ammoniumfunctional groups. According to a specific aspect of the presentinvention, the particles used are based on a copolymer of styrene anddivinylbenzene carrying quaternary ammonium groups. According to oneaspect of the invention, the copolymer of styrene and divinylbenzenecarries trimethylbenzyl ammonium functional groups, which is alsoreferred to as cholestyramine, Cuemid, MK-135, Cholbar, Cholbar,Questran, Quantalan, Colestyramine or Dowex® 1×2-Cl and ascholestyramine from Purolite®. According to another aspect of thepresent invention the anion exchange material is used in the chlorideform.

Anion exchange media which can also be used are known, for example,under the trade name Amberlite®. Amberlite® comprises, for example, amatrix formed of styrene-divinylbenzene having active or functionalgroups such as quaternary ammonium groups, bezyldimethyl(2-hydroxyethyl) ammonium groups or dimethylethanolamine groups. Otheranion exchange media which can be used are known for example, under thetrade name Dowex®. Dowex® comprises, for example, a matrix formed ofstyrene-divinylbenzene which may have active or functional groups suchas trimethylbenzylammonium.

In yet another aspect of the present invention, the particles entrappedin the membrane of the invention are based on vinylimidazoliummethochloride vinylpyrrolidone copolymers, known, for example, asLuviquat®.

According to yet another aspect of the present invention, the particlesmay be uncharged, hydrophobic particles, such as styrenic polymers likeDOWEX™ OPTIPORE™ L493 and V493 or Amberlite® XAD®-2, polydivinylbenzenepolymers or styrene-divinylbenzene copolymers (e.g. Amberlite® XAD4 orAmberchrom™CG161), poly(l-phenylethene-1,2-diyl) (Thermocole), orhydrophobic silica, which is silica that has hydrophobic groupschemically bonded to the surface, or combinations thereof. Hydrophobicsilica can be made both from fumed and precipitated silica. Hydrophobicsilica can be made both from fumed and precipitated silica. Hydrophobicgroups that can be used are, for example, alkyl or polydimethylsiloxanechains. Another hydrophobic material which can be used is known asUjotit, a copolymer of styrene and divinylbenzene without any functionalgroups, which is available as Ujotit PA-30, Ujotit PA-40 or UjotitPA-20. Activated carbon particles which may be used according to theinvention can be derived, for example, from carbon such as Printex® XE2(Degussa AG) or Norit® GAC 1240 PLUS A (Norit Nederland BV).

Cation exchange particles which may be used are generally based onmatrices of agarose, cellulose, dextran, methacrylate, polystyrene orare polyacrylic acid. They are generally known and commerciallyavailable, for example, under trade names such as Sepharose® CM,Sephadex, Toyopearl®, Amberlite®, Diaion™, Purolite®, Dowex® andDuolite® SO₃H, respectively.

In order to obtain the doped membranes of the present invention, it isimportant to provide a method of grinding which allows the preparationof particles with an average particle size of below 20 μm or below 15μm, e.g. of between 0.1 and 10 μm, wherein the particles will notre-form or agglomerate into larger particles during or after grindingand during the formation of the spinning solution and/or the spinningprocess itself. In other words, the method of grinding and subsequentformation of a spinning solution must ensure the maintenance ofparticles with said average size of about 0.1 to 15 μm.

According to one aspect of the present invention, the particles used arebased on gel ion exchange material (gel resins). For example, Dowex®1×2-Cl is provided as a gel with a particle size of between 100 and 200mesh. The general particle size of, for example, the before-mentionedanion exchange material is in the range of 20 to 400 mesh (μm) dependingon the specific starting material. Most ion exchange materials such asanion exchange material are provided as gels. Gel resins generally havehigher ion capacity compared to e.g. microporous resins. Such ionexchange resins are hygroscopic, wherein the amount of moisture hydratedby the material depends on the cross-linking and the type of functionalgroup. Low cross-linking gel resins with functional groups such asquaternary ammonium contain large amounts of water resulting inswelling. The addition and removal of water thus results in swelling andcontraction. The hygroscopic and swelling properties of the materialseverely influence the grinding process and especially the formation ofthe spinning solution and the following spinning process. Tests couldshow that the dry grinding of the ion exchange material which was donein the absence of additional water resulted in fine particles in thedesired range of about 1 to 7 μm. However, the particles swelled uponaddition to a standard polymer solution comprising, among othercomponents, water. In addition, the particles were shown to agglomerate,especially upon adding the particles to spinning solutions which containwater. The particles finally present in the polymer solution were foundto have a size of again up to 20-30 μm and were deposited in such sizein the membrane during spinning (see Examples 1, 2.2, 3 and 6), even ifthe addition of the particles to the spinning solution or vice versa wasdone very slowly. As a consequence, the spinning of the membranes isdifficult and often is interrupted as the nozzles get clogged by thelarger particles, in which case the spinning is interrupted and thefiber is torn. In the resulting membranes, the particles are wellvisible within a cavity or void formed by the water which is abundant inthe particle, as can be seen in the SEM as shown in FIG. 3. Furthermore,the large particles being close to or penetrating the outer or innersurface of the membrane destabilize the membrane and are prone to bewashed out of the membrane structure. The efficacy and usefulness ofsuch membranes for removing or adsorbing the targeted substances from aliquid is thus limited.

It could now be shown that it is important for avoiding such problems toperform the grinding of the particles in an aqueous solution or in asolution comprising water and an organic solvent. The organic solventusually will be the organic solvent also used for forming the spinningsolution. As a result, a suspension comprising particles, water and,optionally, organic solvent, is formed. The amount of water used forforming the suspension may vary.

According to one aspect of the present invention, water should be addedin an amount which corresponds to the amount of water which is neededfor forming the spinning solution. In other words, the complete amountof water which would otherwise be a component of the spinning solutionis already added to the ion exchange material for grinding. Anyinfluence of water which is added at a later stage, for example duringthe formation of the final spinning solution, is thus avoided. However,it is also possible to add only a portion of the complete amount ofwater to the grinding process, as long as the amount of water sustainsthe forming and maintenance of the particles of the intended sizeaccording to the invention and avoids further swelling and/oragglomeration of the particles.

According to another aspect of the invention, the water is supplementedby an organic solvent, wherein the solvent is chosen according to theorganic solvent which is otherwise used for forming the membranespinning solution. Such organic solvent can be chosen from the groupcomprising, for example, N-alkyl-2-pyrrolidones (NAP) such asN-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP),N-octyl-2-pyrrolidone (NOP); dimethyl acetamid (DMAc); dimethylformamide(DMF); dimethylsulfoxide (DMSO); formamide; THF; butyrolactone;especially 4-butyrolactone; and ε-caprolactam or mixtures thereof.However, any other organic solvent may be used in the process which isalso used as an organic solvent for the preparation of syntheticmembranes. Such organic solvents are generally known in the art.According to one aspect of the present invention, a mixture of water andNMP is used for grinding the ion exchange material.

According to another aspect of the invention, polyvinylpyrrolidone (PVP)can be added to the grinding solution in addition to the water and theoptional organic solvent. The PVP concentration may vary. In general,the PVP concentration will be determined by the composition of the finalpolymer spinning solution. Particles for doped membranes based onpolymer compositions which comprise PVP can thus be grinded in asolution which may include PVP in a concentration of up to the totalamount of PVP which will be added to the polymer spinning solution. Forexample, a membrane without particles may consist of 80-99% by weight ofa hydrophobic polymer, such as polyethersulfone, and 1-20% by weight ofa hydrophilic polymer, such as polyvinylpyrrolidone. The PVP consists ofa high (≧100 kD) and low (<100 kD) molecular component, wherein the PVPconsists of 10-45 weight-%, based on the total weight of PVP in themembrane, of a high molecular weight component, and of 55-90 weight-%,based on the total weight of PVP in the membrane, of a low molecularweight component. The spinning solution for preparing a membraneaccording to the present invention comprises, for example, between 12and 19 weight-% of a hydrophobic polymer and 5 to 12 weight-% of PVP,wherein said PVP consists of a low and a high molecular PVP component.Examples for high and low molecular weight PVP are, for example, PVPK85/K90 and PVP K30, respectively. PVP was found to stabilize thegrinding suspension and foster the maintenance of the particles at thedesired size.

It is another aspect of the present invention that the grinding time canbe significantly reduced by such grinding process. In addition, theenergy expenditure is also significantly reduced as, surprisingly, thesofter material proved to be grinded more readily in a process accordingto the invention. Usually, brittle or recalcitrant material is bettersuited for grinding.

Various grinding mills can be used for a grinding process according tothe invention. Such mills should be able to control pressure,temperature and energy input. Agitator bead mills are commerciallyavailable, for example, from manufacturers such as Nitzsch, HosokawaAlpine or WAB. For example, the LABSTAR mills of Nitzsch, which aregenerally used for laboratory scale applications, can be used inaccordance with the present invention. The achieved process data for thespecific grinded material can then be used for a scale up and may beapplied for production machines available from the same producer.

According to one aspect of the present invention, the membrane mayeffectively be used for removing or purifying from a liquid substanceswhich bind to or are adsorbed to the material which is entrapped in themembrane according to the invention. According to one aspect, themembranes of the invention are used for the removal or purification ofnucleic acids from a liquid. According to another aspect, the membranesof the invention are used for the removal or purification of certaintarget substances, comprising endogenous and/or exogenous toxins, from aliquid. Such liquid may comprise, for example, whole blood, bloodproducts such as, for example, blood fractions like blood plasma, cellculture suspensions or their supernatant and/or any fractions thereof,and solutions based on water, organic solvents or mixtures thereof andfrom which one or more compounds are to be removed or purified from andwhich will bind or adsorb to the hydrophobic or hydrophilic material,such as ion exchange or activated carbon particles, with which themembrane has been doped. The material to be entrapped in the membranewill have to be chosen according to the target compounds which shall beremoved or purified from the liquid in question.

The membranes of the invention may be prepared and used in variousgeometries, such as, for example in hollow fiber geometry. The membranesmay also be prepared as flat sheet membranes. It is also possible toprepare solid membranes. According to one aspect of the invention, thewall thickness of the hollow fiber membrane is below 150 μm. In anotheraspect of the invention, the inner diameter of a solid or hollow fibermembrane is below 400 μm, generally between 250 μm and 400 μm.

According to another aspect of the invention, the membrane is used forthe removal, adsorption, isolation and/purification of certain compoundsfrom blood or blood products, such as, for example, blood plasma.According to yet another aspect of the invention, the membrane is usedfor the removal, adsorption, isolation and/purification of certaincompounds from aqueous solutions, such as, for example, water ordialysate.

According to one aspect of the invention, the membranes arecharacterized in that they have particles entrapped therein, wherein theparticles may consist of activated carbon particles and/or hydrophobicparticles based on styrene-divinylbenzene copolymers and/or ion exchangematerial, such as cation exchange material or anion exchange material,for example anion exchange material based on polyquaternary ammoniumfunctionalized styrene divinylbenzene copolymers.

According to another aspect, the invention relates to membranes whichare characterized in that they have particles entrapped therein, whereinthe particles consist of basic anion exchange material based onpolyquaternary ammonium functionalized vinylimidazolium methochloridevinylpyrrolidone copolymers, such as, for example, Luviquat®.

According to a further aspect of the present invention, thepolyquaternary ammonium functionalized styrene divinylbenzene copolymersand vinylimidazolium methochloride vinylpyrrolidone copolymers arefunctionalized with at least one quaternary ammonium selected from thegroup consisting of dimethyl(2-hydroxyethyl) ammonium, trimethylbenzylammonium, dimethylethanolbenzyl ammonium, dimethylethanol ammonium andbenzyltriethyl ammonium. According to yet another aspect of the presentinvention, the functionalized polyquaternary ammonium copolymer is usedin its chloride form for preparing and providing the membrane of theinvention.

According to another aspect of the present invention the particles makeup for 5-40 wt.-% of the total membrane mass. According to yet anotheraspect of the present invention, the particles are present in an amountof between 20 to 35 wt.-% of the total membrane.

According to another aspect of the present invention, the particles havean average size of below 15 μm in diameter. According to yet anotheraspect of the present invention, the particles have an average size ofbetween 0.1 and 10 μm in diameter. According to yet another aspect ofthe present invention, the particles have an average size of between 0.1and 1.0 μm in diameter.

According to a further aspect of the present invention, the membrane isotherwise comprised of at least one hydrophobic polymer selected fromthe group consisting of polysulfones, polyethersulfones, polyamides andpolyacrylonitriles and at least one hydrophilic polymer. According toyet another aspect of the present invention, the hydrophilic polymer isselected from the group consisting of polyvinylpyrrolidone (PVP),polyethylene glycol (PEG), polyglycolmonoester, water soluble cellulosicderivates, polysorbate and polyethylene-polypropylene oxide copolymers.The particle content in the polymer spinning solution may vary.According to one aspect, the particle content is from about 0.1 to 12wt.-% of the spinning solution. According to another aspect, theparticle content in the spinning solution is from 1 to 10 wt.-% of thespinning solution. According to yet another aspect of the invention, theparticle content is from 1 to 8 wt.-% of the spinning solution.

According to one aspect of the present invention, the doped membranes ofthe invention are microporous membranes. Microporous membranes are knownin the art and can be prepared, for example, according to what isdisclosed in EP 1 875 957 A1, incorporated herein by reference. Theexpression “microporous” as used herein refers to membranes which arecharacterized by an average pore diameter of the selective separationlayer in the membrane in the range of 0.1 to 10 μm, preferably 0.1 to1.0 μm.

According to one aspect of the present invention, doped microporoushollow fibre membranes can be prepared in a process comprising the stepsof extruding a polymer solution through the outer ring slit of a hollowfibre spinning nozzle, simultaneously extruding a centre fluid throughthe inner bore of the hollow fibre spinning nozzle, into a precipitationbath, whereby the polymer solution contains 0.1 to 10 wt.-% ofhydrophobic and/or ion exchange particles, 10 to 26 wt-% of ahydrophobic polymer, such as polysulfone (PSU), polyethersulfone (PES)or polyarylethersulfone (PAES), 8 to 15 wt-% polyvinylpyrrolidone (PVP),55 to 75 wt-% of a solvent such as, for example, NMP, and 3 to 9 wt-%water. The centre fluid contains 70 to 90 wt-% of a solvent such as, forexample, NMP, and 10 to 30 wt-% water, and the precipitation bathcontains 0 to 20 wt-% of a solvent such as, for example, NMP, and 80 to100 wt-% water.

According to another aspect of the present invention, the dopedmembranes of the invention are ultrafiltration membranes. Membranes ofthis type can be characterized by a pore size, on the selective layer,of from about 2 to 6 nm as determined from dextran sieving experiments.The preparation of ultrafiltration membranes is known in the art and aredescribed in detail, for example, in U.S. Pat. No. 4,935,141, U.S. Pat.No. 5,891,338 and EP 1 578 521 A1, all of which are incorporated hereinby reference. According to one aspect of the invention, dopedultrafiltration membranes according to the invention are prepared from apolymer mixture comprising particles and hydrophobic and hydrophilicpolymers in amounts such that the fraction of hydrophobic polymer in thepolymer solution used to prepare the membrane is from 5 to 20% by weightand the fraction of the hydrophilic polymer is from 2 to 13% by weight.

According to another aspect of the present invention, the polymersolution for preparing a membrane according to the invention comprisesfrom 0.1-8 wt.-% of ion exchange and/or hydrophobic particles, 11 to 19wt.-% of a first polymer selected from the group consisting ofpolysulfone (PS), polyethersulfone (PES) and polyarylethersulfone(PAES), from 0.5 to 13 wt.-% of a second polymer such aspolyvinylpyrrolidone (PVP), from 0 wt.-% to 5 wt.-%, preferably from0.001 to 5 wt.-% of a polyamide (PA), from 0 to 7 wt.-% of water and,the balance to 100 wt.-%, of a solvent selected from the groupconsisting of N-methyl-2-pyrrolidone (NMP), which is preferred,N-ethyl-2-pyrrolidone (NEP), N-octyl-2-pyrrolildone (NOP), dimethylacetamide, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) andgammabutyrolactone (GBL).

In yet another aspect of the present invention, the polymer solutionused to prepare the membrane of the invention comprises in addition tothe particles contained in the doped membrane from 12 to 15 wt.-%polyethersulfone or polysulfone as hydrophobic polymer and from 5 to 10wt.-% PVP, wherein said PVP consists of a low and a high molecular PVPcomponent. The total PVP contained in the spinning solution consists offrom 22 to 34 wt.-%, preferably of from 25 to 30 wt.-%, of a highmolecular weight (>100 kDa) component and from 66 to 78 wt.-%,preferably from 70 to 75 wt.-% of a low molecular weight (<=100 kDa)component. Examples for high and low molecular weight PVP are, forexample, PVP K85/K90 and PVP K30, respectively. The polymer solutionused in the process of the present invention preferably furthercomprises from 66 to 86 wt.-% of solvent and from 1 to 5 wt.-% suitableadditives. Suitable additives are, for example, water, glycerol and/orother alcohols. Water is especially preferred and, when used, is presentin the spinning solution in an amount of from 1 to 8 wt.-%, preferablyfrom 2 to 5 wt.-%. The solvent used in the process of the presentinvention preferably is chosen from N-methylpyrrolidone (NMP), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF),butyrolactone and mixtures of said solvents. NMP is especiallypreferred. The center fluid or bore liquid which is used for preparingthe membrane comprises at least one of the above-mentioned solvents anda precipitation medium chosen from water, glycerol and other alcohols.Most preferably, the center fluid consists of 45 to 70 wt.-%precipitation medium and 30 to 55 wt.-% of solvent. Preferably, thecenter fluid consists of 51 to 57 wt.-% of water and 43 to 49 wt.-% ofNMP. Methods for preparing such membranes are disclosed in detail inEuropean Patent Application No. 08008229, incorporated herein byreference.

According to yet another aspect of the present invention, the dopedmembranes of the invention are so called protein separation membranes,sometimes also referred to as “plasma purification or “plasmafractionation membrane”. Such membrane is characterized by allowing thepassage of ≧90% of molecules having a molecular weight of below 100 kD,while molecules having a molecular weight of >1000 kD will pass themembrane wall only to a very limited extend (≦10%). The membrane thusallows to separate plasma in fractions with mainly largerproteins/lipids and smaller proteins, such as, for example, albumin.Membranes of this type are known and also commercially available, forexample the “Monet®” filter (Fresenius Medical Care Deutschland GmbH).

According to one aspect of the present invention, the membranes havehollow fiber geometry. According to another aspect of the presentinvention, the membranes have flat sheet geometry.

It is another object of the present invention to provide a method forpreparing the membrane of the invention in hollow fiber geometry,wherein the method comprises (a) grinding the particles to an averagesize of up to 15 μm in an aqueous solution which optionally alsocomprises PVP and/or an organic solvent; (b) optionally furthersuspending the grinded particles in an organic solvent; (c) combiningthe at least one hydrophilic and the at least one hydrophobic polymerwith the suspension of step (a) or (b); (d) stirring the polymerparticle suspension to obtain a polymer solution wherein the particlesare suspended; (e) degassing the polymer particle suspension; (f)extruding the polymer solution together with the suspended particlesthrough an outer ring slit of a nozzle with two concentric openings,wherein a center fluid is extruded through the inner opening of thenozzle; (g) optionally exposing the polymer solution on the outside ofthe precipitating fiber to a humid steam/air mixture comprising asolvent in a content of between 0 and 10% by weight related to the watercontent; (h) immersing the precipitating fiber in a bath of non-solvent;(i) washing and optionally drying and sterilizing the membrane.

It is another object of the present invention to provide a method forpreparing the membrane of the invention in flat sheet geometry, whereinthe method comprises (a) grinding the particles to an average size of upto 15 μm in an aqueous solution, optionally in the presence of PVPand/or an organic solvent; (b) optionally further suspending theparticle solution in organic solvent; (c) combining the at least onehydrophilic and the at least one hydrophobic polymer with the suspensionof step (a) or (b); (d) stirring the polymer particle suspension toobtain a polymer solution wherein the particles are suspended; (e)degassing the polymer particle suspension; (f) casting the polymersolution together with the suspended particles as an uniform film onto asmooth surface; (g) washing the membrane and optionally drying and/orsterilizing the membrane.

In yet another aspect of the present invention, it is of course possibleto create hollow fiber membranes based on the present invention, whereinthe membranes have multiple layers which are concentrically arranged andwherein at least one of the layers comprises 5-40 wt.-% of particleshaving an average particles size of below 15 μm entrapped in themembrane according to the invention. The layer adjacent to the layercontaining ion exchange and/or carbon particles is preferably the onewhich contacts the blood in applications which involve the treatment ofblood or blood components, e.g. in an extracorporeal system. Like that,the risk of any particles being washed out of the membrane is minimized.It is also possible to have adjacent layers to the outer and innersurface of the particle containing layer. The multi layer membranes canbe produced in analogy to what is disclosed in WO 2006/019293 A1, whichis incorporated herein by reference.

EXAMPLES Example 1 Grinding of Ion Exchange Resin in the Presence andAbsence of Water

Grinding was performed with a LabStar LS1 grinding mill of Netzsch.Dowex® 1×2 anion exchanger was grinded in two separate batches A and Bin the presence of water and NMP as an organic solvent (see also FIGS.4A and 4B, corresponding to Batch B and Batch A, respectively). Batch Cwas grinded in the absence of water. Table I summarizes the settings forthe grinding procedure.

TABLE I Batch A Batch B Batch C (RF070205A) (RF070207A) (RF061106A) Ionexchange Dowex ® Dowex ® Dowex ® material 1x2-Cl, 1x2-Cl, 1x2-Cl, 1000 g500 g 500 g Solvent Water/NMP Water/NMP NMP (247.1 g/1300 g) (247.1g/1300 g) (2000 g) Agitator 3000 1/min 3000 1/min 3000 1/min speedThroughput 74 kg/h 76 kg/h 60 kg/h Energy input 3.99 kWh 1.81 kWh 7.96kWh Grinding Zirconium Zirconium Zirconium material oxide oxide OxideFiller 90% 90% 90% Loading Treatment 120 min 60 min 300 min timeParticle diam- d99 = 7.6 μm d99 = 5.9 μm d99 = 8.0 μm eter on cu-mulative %

The process data were collected for controlling energy input, pump speedand the resulting average size of the grinded particles. FIG. 4 showsthe results for the above batches of Table I. As can be seen, Batch Aresulted in particles with q99%:7.6 μm. Batch B resulted in particleswith q99%:5.9 μm. A considerable portion of the particles in Batches Aand B, in the presence of water, have a diameter of well below 1 μm.

Comparative Batch C (see also FIG. 5) resulted in particles withq99%:8.0 μm, which per se was a satisfying result with regard to thegoal of having particles of at least below 15 μm. However, the resultingparticles of Batches A and B were already swollen. The particles ofBatch C, however, had not yet been contacted with the water present inthe spinning solution (see Example 2.2).

Example 2 2.1 Preparation of a Spinning Solution which ContainsParticles Grinded in the Presence of Water

The particles of Batch A (see Example 1) were used for the preparationof a spinning solution for preparing a microporous doped membrane. Thepolymer composition was chosen to be a combination of hydrophobicpolyethersulfone (PES) and a mixture of polyvinylpyrrolidone having highmolecular weight (PVP K85) and low molecular weight (PVP K30). Thespinning solution further comprised NMP as a solvent and water.

Batch A (2414.48 g) was comprised, after grinding, of anion exchangeparticles (19.88%), NMP (65.21%) and H₂O (14.91%). This suspension wasfilled into a glass reactor and 1362.97 g NMP were added. The suspensionwas stirred at U=600 min⁻¹ until the suspension was homogenous. This wasfollowed by a one hour treatment, under stirring, with an ultrasonicdevice of Hielscher (UP 400S) for the homogenization and deagglomerationof the suspension. The UP 400S was set to Cycle 1, Amplitude 45% and anenergy input of 150 W.

PVP K85 (180 g) was then added to the suspension and the stirrer was setto 1000 min⁻¹. The PVP K85 was dissolved under stirring and ultrasoundfor one hour. 360 g PVP K30 were then added and also dissolved understirring and ultrasound. 960 g PES were then added and after 15 minutesthe ultrasound device was removed. The stirring velocity was adapted tothe apparent viscosity of the suspension. After the PES had completelybeen solved the average particle size was determined in a particlecounter. To this end, 100 μl of the solution were taken and added to 600ml NMP in a glass bottle. The sample was stirred for about 15 to 20minutes. The particle counter was set as follows. Channel setting:16/2-100 μm, sample volume; 5 ml; flow rate: 60 ml/min; number of runs:9; dilution factor: 1.0; discard first run. No particles larger thanabout 15 μm could be detected in the spinning solution.

The spinning solution ready for spinning was comprised of (wt.-%)grinded Dowex® 1×2 anion exchanger: 8%; NMP: 61%; PVP K85: 3%; PVP K30:6%; PES: 16%; H₂O: 6%.

The spinning solution comprising the particles of Batch B was preparedaccordingly. Batch (1622.9 g) B contained, after grinding, grindedDowex® 1×2 particles (17.75%, NMP: 68.87% and water (13.35%). NMP(1083.82 g) was added to the suspension which was treated as describedabove for Batch A and PVP K85 (108.27 g), PVP K30 (216.54 g) and PES(577.44 g) were added. No particles larger than about 15 μm could bedetected in the spinning solution. The spinning solution ready forspinning was comprised of (wt.-%) grinded Dowex® 1×2 anion exchanger:8%; NMP: 61%; PVP K85: 3%; PVP K30: 6%; PES: 16%; H₂O: 6%.

2.2 Preparation of a Comparative Spinning Solution which ContainsParticles Grinded in the Presence of Organic Solvent

The anion exchanger particle suspension of Example 2 (Batch C) aftergrinding contained NMP (222.07) and 25 wt.-% of the anion exchangeparticles (191.92 g). The suspension was treated with ultrasound asdescribed in Example 2.1 for 1 h. Several batches were treated(separately) in order to guarantee an optimal homogenization anddeagglomeration. The treated suspensions were then transferred to athree-necked flask. The final content of NMP in the flask was set to atotal of 1830 g NMP (61 wt.-% of the final polymer solution) and 239.9 gof the anion exchange material (8% of the final polymer solution). PVPK85 (90 g) was slowly added to the solution (3% of the final polymersolution), followed by the careful addition of 180 g PVP K30 (6% of thefinal polymer solution). Ultrasound treatment was applied until the PVPcomponents had completely dissolved. Then PES (480 g) was added slowly(16% of the final polymer solution) at a temperature of 45° C. Finally,H₂O (180 g) was carefully added (6% of the final polymer solution).

The control of the particle size after each step gave the followingresults: (1) after mixing particles and NMP: d99=20 μm; (2) afteraddition of PVP K85: d99=30 μm; (3) after addition of PVP K30: d99=30μm; (4) after addition of PES: d99=25 μm; (5) after complete addition ofwater: d99=30 μm. The polymer solution was then used for spinning.

Example 3 Preparation of Doped Hollow Fiber Membranes

Spinning of hollow fibers was done as described in the art for allpolymer solutions of Example 2. The polymer and solvent components usedfor the various membranes are set forth again in Table II, whereinsamples 2-3a were prepared with the spinning solution containing Batch Aparticles (Ex. 1 and 2.1) and samples 4-5 were prepared with thespinning solution containing Batch B particles (Ex. 1 and 2.1). Sample 1was prepared from a spinning solution according to Ex. 2.2 comprisingparticles as described in Ex. 1 (Batch C). Table II also shows thecomposition of the center fluid which was used for the spinning process.

TABLE II Polymer solution PVP PVP DOWEX Center PES K85 K30 1X2 H₂O NMPViscosity H₂O NMP Samples % % % % % % cP % % 1 16 3 6 8 6 61 ~200000 2278  2-3a 110000 4-5 112200

For the spinning process, the respective polymer solutions of Example 2were transferred into stable stainless steel containers. The containerswere closed and vacuum was applied for degassing the solutions. Thesolution was degassed and then heated to 50° C. and passed through aspinning die (1200×440×220 μm) into the precipitation bath. As centerfluid, a mixture of 22% H₂O and 78% NMP was used (Table II). Thetemperature of the die (SD) and of the spinning shaft (SS) can bederived from Table III. The hollow fiber membrane was formed at aspinning speed of between 13.0 and 13.2 m/min (see Table III). Theliquid fiber leaving the die was passed into a heated precipitation(water) bath having a temperature of about 65° C. (see Table III). Thefiber, at leaving the die, was surrounded by water vapor from theprecipitation bath. The distance between the exit of the die and theprecipitation bath was 7 to cm (see Table III). The precipitated fiberwas guided through several water baths and subjected to online-dryingfollowed by undulation of the fiber. The fibers were transferred intobundles.

The resulting hollow fiber membranes had an inner diameter of between375 and 388 μm and a wall thickness of between 116 and 122 μm (see TableIV).

TABLE III Spinning Parameters Distance Precipitation Spinning to WaterBath Temperature Speed Bath T NMP Spinning Spinning Sample [m/min] [cm][° C.] [%] Nozzle Shaft 1 13 8¹ 55 0 50 50 2 13 8¹ ca. 65 0 46 52-54 313.2 7² ca. 65 0 47 54  3a 13.2 7² ca. 64 0 46 53 4 13.2 7² ca. 65 0 4754 5 13.2 7² ca. 65 0 48 54 ¹Spinning shaft with 1 cm distance to watersurface. ²Spinning shaft directly on water surface.

TABLE IV Dimensions Inner diameter Wall thickness Sample μm μm 1 380 1202 385 118 3 383 116  3a 380 115 4 375 122 5 388 118

Example 4 Preparation of Hollow Fiber Membranes Doped with Amberlite®IRA 410 or PEI, Dowex® 1×2 Anion Exchanger Plus Carbon Particles

Doped microporous hollow fiber membranes were prepared according toExample 3, wherein polyethyleneimine (PEI, see Samples 1-12, 14-16 inTable Va) and both grinded Dowex® 1×2 anion exchange particles andhighly conductive carbon black particles Printex® XE2 (Degussa AG), seeSamples 13, 17-24 in Table V, were entrapped in the membrane. Thepreparation of the spinning solution was done as described before inExample 2.1. The polymer composition was as set forth in Table V. TableVI summarizes the spinning parameters which were applied for theproduction of this double-doped membrane. Samples 1-16 were online driedand subjected to an undulation of the fibers. For Samples 1-16 standard500×350×170 μm were used. For the rest, 1200×440×220 μm spinning nozzleswere used.

TABLE V Polymer Solution PVP PVP DOWEX ® Center PAES K85 K30 1X2PRINTEX ® H₂O NMP PEI H₂O NMP Sample % % % % XE2 % % % % % 1 17.75 3 8 00 0.96 69.99 0.3 46 54 2 17.75 3 8 0 0 0.96 69.99 0.3 44 56 3 17.75 3 80 0 0.96 69.99 0.3 42 58 4 17.75 3 8 0 0 0.96 69.99 0.3 40 60 5-12,17.75 3 8 0 0 0.96 69.99 0.3 38.5 61.5 14-16 13, 17 3.25 7 4 0 6 62.75 022 78 17-19 20-22 16 3 6 8 0 6 61 0 22 78 23, 24 16 3 6 7 1 6 61 0 22 78

Hollow fiber membranes which contained Amberlite® IRA-410 particles wereprepared accordingly, based on the following polymer compositions (TableVb). Samples 10-13 were prepared for comparative reasons without anyAmberlite® IRA-410 particles. Triple spinnerets were used for Samples10-16. Other spinnerets used were a 600×305×170 μm spinneret for Samples2 and 6-9, a 500×350×170 μm spinneret for Sample 1 and a 1200×440×220for Samples 3-5. Spinning was done as summarized in Table VIb. Innerdiameter and wall thickness are also shown in Table VIb. DNA retentioncapability (adsorption) was measured with salmon sperm DNA (c=40 μg/ml,dialysate, RT, Q=1.9 ml/min, t=50 min). The results are shown in FIG. 8in comparison to a membrane without any entrapped Amberlite® IRA-410. Itcan be seen that the presence of the ion-exchanger leads to a clearreduction of the DNA concentration.

TABLE Vb Polymer Solution Center PVP PVP Amberlite ® PVP PES K90 K30IRA-410 H₂0 NMP H₂0 K90 NMP Sample [%] [%] [%] [%] [%] [%] [%] [%] [%] 113.1 1.9 4.8 3.9 2.9 73.4 56 0 44 2 13.5 1.5 5 1.3 3 75.7 56 0 44 3 13.31.5 4.9 2.7 2.9 74.7 56 0 44 4 13.3 1.5 4.9 2.7 2.9 74.7 56 0 44 5 13.31.5 4.9 2.7 2.9 74.7 56 0 44 6 13.1 1.5 4.8 3.9 2.9 73.8 56 0 44 7 13.11.5 4.8 3.9 2.9 73.8 56 0 44 8 13.1 1.5 4.8 3.9 2.9 73.8 56 0 44 9 17.12.9 6.6 5.1 0 68.3 43 0 57 10 13.6 2 5 0 3 76.4 56 0 44 11 13.6 2 5 0 376.4 56 0 44 12 13.6 2 5 0 3 76.4 56 0 44 13 13.6 2 5 0 3 76.4 56 0 4414 13.6 2 5 1.36 3 75.04 56 0 44 15 13.6 2 5 1.36 3 75.04 56 0 44 1613.6 2 5 1.36 3 75.04 56 0 44

TABLE VI Spinning Conditions Precipitation Distance to bath Temperaturev_(ab) water bath T NMP SK SS Sample [m/min] [cm] [° C.] [%] ° C. ° C. 110 4 30 80 60 — 2 10 4 30 80 60 — 3 10 4 31 80 60 — 4 10 4 31 80 60 — 510 4 31 80 57 — 6 10 4 31 80 60 — 7 10 4 31 80 63 — 8 10 4 31 80 66 — 910 4 30 80 49 — 10 10 4 30 80 51 — 11 10 4 30 80 53 — 12 10 4 30 80 56 —13 13  8¹ 51 0 50 ~46 14 10 4 30 80 55 — 15 10 4 30 80 57 — 16 10 4 3080 59 — 17 13  8¹ 51 0 50 ~45 18 13  8¹ 51 0 50 ~45 19 13  8¹ 51 0 50~45 20 13  8¹ 52 0 50 ~46 21 13  8¹ 57 0 50 ~48 22 13  8¹ 56 0 50 ~48 2313  8¹ 51 0 50 ~45 24 13  8¹ 57 0 50 ~49 ¹hot precipitation bath with 1cm distance to the bath

The dimensions of the fibers with Dowex® 1×2 and Printex® XE2 particlesare shown in Table VII. It was possible to reduce the wall thicknessesto about 50 μm for fibers with PEI and to about 70 to 80 μm for fiberswith Dowex® 1×2 anion exchange particles and carbon black particlesPrintex® XE2.

TABLE VIb Temper- Temper- Dimensions Distance ature ature Inner Wall toprecip. Spinning Spinning Diam- Thick- Sam- bath v_(ab) Nozzle Shafteter ness ple [cm] [m/min] [° C.] [° C.] [μm] [μm] 1 100 20 51 45 nd nd2 100 20 51 45 254 53 3 100 17 51 45 270 88 4 100 17 51 45 274 92 5 10017 53 48 265 92 6 100 17 51 45 256 75 7 100 18 53 48 257 73 8 100 18 5348 243 70 9 68 17 47 45 318 50 10 100 45 55 50 212 48 11 100 45 55 50212 48 12 100 37 57 52 211 74 13 100 37 57 52 211 74 14 80 37 58 55 21371 15 80 37 58 55 213 71 16 100 45 55 50 211 53

TABLE VII Dimensions Inner diameter Wall thickness Sample μm μm 1 214 502 218 50 3 213 50 4 216 51 5 215 51 6 218 52 7 215 48 8 218 50 9 217 5110 217 52 11 215 51 12 213 51 13 320 50 14 219 50 15 213 52 16 215 50 17321 50 18 323 79 19 321 50 20 318 77 21 317 78 22 258 80 23 321 78 24326 77

Example 5 Preparation of Flat Sheet Membranes Containing Luviquat® FC370 Particles

Doped flat sheet membranes containing Luviquat® FC 370 (BASF AG)particles (poly[(3-methyl-1-vinylimidazoliumchloride)-co-(1-vinylpyrrolidone)]polyquaternium), were prepared. Thepolymer solution contained 13.6 wt.-% PEAS, 2.0 wt.-% PVP K90, 5.0 wt.-%PVP K30 and 79.4 wt.-% NMP. All components were dissolved in NMP andstirred at 60° C. The suspension was additionally filtered (50 μm). Theprecipitation solution, having a temperature of 50° C., contained 56wt.-% water and 44 wt.-% NMP. The final polymer solution was cast asuniform film onto a smooth surface (glass slide) which acted assupporting area by utilizing a special coating knife. First, the polymersolution at 60° C. was directly applied steady-going onto the glassslide using a syringe. The coating knife was driven with a constantvelocity, thus creating a uniform polymer film. This glass slide withthe thin polymer film was quickly dipped into the precipitation bath.Subsequently, the precipitated membrane was taken out, stored innon-solvent until all membranes of a series were prepared and then cutinto a defined size. After cutting, the membranes were washed withdistilled water, dried and finally packed in special bags used forsterilization.

Example 6 Preparation of Flat Sheet Membranes Doped with Amberlite®IRA-410 (Comparative Example)

Doped flat sheet membranes were prepared according to Example 5, whereinAmberlite® IRA-410 (chloride form) particles were entrapped in themembrane at different concentrations (0%, 30% and 50%). The Amberlite®particles were suspended in water and grinded and the material waspassed through a PE net (50 μm and 20 μm) in order to remove particleswith a size of above 20 μm. The excess water was then removed in avacuum rotary evaporator and NMP was added, followed by anothertreatment with the vacuum rotary evaporator for the removal of remainingwater. The other components of the polymer solution were then added tothe NMP suspension (see Table VIII). An agglutination of the particleswas visible at that stage already.

Example 7

Preparation of Membranes Doped with Modified Poly(p-phenylene ether)(PPE)

Doped microporous hollow fiber membranes were prepared according toExample 3, wherein modified PPE was added to the membrane asanion-exchanger. The modified PPE (FUMA-Tech GmbH, St. Ingbert, 5 or 15%solution) was produced by bromination of PPE, dissolving it in NMP andreacting it with N-methylimidazole. The resulting structure is asfollows:

The polymer composition was as set forth in Tables VIII. Table VIII (a)shows the composition for preparing an ultrafiltration membrane with(a1-a3) and without (a4) anion exchange component. The resultingmembrane was prepared as shown in Table VIII (b). The inner diameter wasabout 213-217 μm and the wall thickness about 48-50 μm. Then, the DNAretention was compared (Table VIII (c)) with the help of mini-modules.Again, salmon sperm DNA (40 mg/1) was used, dead end filtration at 2ml/min, t=100 min. The retention of DNA could be improved by the anionexchanger.

TABLE VIII(a) Polymer Center mod. PVP PVP PVP Sam- PAES PPE K90 K30 H₂0NMP H₂0 K30 NMP ple % % % % % % % % % a1 13.72 0.28 2 5 2 77.0 56 1 43a2 13.72 0.28 2 5 2 77.0 55 1 44 a3 13.72 0.28 2 5 2 77.0 54 1 45  a4*13.55 0 2 5 3 76.4 56 1 43 *with 0.05% polyamide

TABLE VIII (b) Distance Temperature v_(ab) to water Spinning SpinningSample [m/min] bath [cm] Nozzle Shaft a1 45 100 55 50 a2 45 100 58 53 a345 100 58 53 a4 45 100 54.5 48.5

TABLE VIII(c) Sample DNA-Adsorption [%] a1 50 a4 28

Table VIII (d) shows the composition for preparing a microporousmembrane with modified PPE (Table VIII (e)). The inner diameters were258 and 259 μm for b1 and b2, respectively, with a wall thickness of 40and 42 μm. The DNA retention was again assessed (Table VIII (f)) withmini-modules as described before and compared with the ultrafiltrationmembrane a4 which was prepared as described before in Tables VIII (a)and (b). Again, the DNA retention capability was clearly improved.

TABLE VIII(d) Polymer Center mod. PVP PVP PVP Sam- PAES PPE K90 K30 H₂0NMP H₂0 K30 NMP ple % % % % % % % % % b1 16.7 1.3 3.25 8 0 70.75 43 0 57b2 16.7 1.3 3.25 8 0 70.75 43 0 57

TABLE VIII(e) Distance Temperature v_(ab) to water Spinning SpinningSample [m/min] bath [cm] Nozzle Shaft b1 28 60 45 43 b2 28 60 47 45

TABLE VIII(f) Sample DNA-Adsorption [%] b2 73 a4 30

Example 8 Preparation of Hand Bundles and Mini-Modules

The preparation of a membrane bundle after the spinning process isnecessary to prepare the fiber bundle for following performance tests.The first process step is to cut the fiber bundles to a defined lengthof 23 cm. The next process step consists of melting the ends of thefibers. An optical control ensures that all fibers are well melted.Then, the ends of the fiber bundle are transferred into a potting cap.The potting cap is fixed mechanically and a potting tube is put over thepotting caps. Then the fibers are potted with polyurethane. After thepolyurethane has hardened, the potted membrane bundle is cut to adefined length and stored dry before it is used for the differentperformance tests.

Mini-modules [=fiber bundles in a housing] are prepared in a similarmanner. The mini-modules ensure protection of the fibers and are usedfor steam-sterilization. The manufacturing of the mini-modules comprisesthe following specific steps:

-   (A) The number of fibers required is calculated for an effective    surface A of 360 cm² according to equation (1)

A=π×d _(i) ×l×n[cm ²]  (1)

-   -   Wherein d_(i) is the inner diameter of fiber [cm], n represents        the amount of fibers, and 1 represents the effective fiber        length [cm].

-   (B) The fiber bundle is cut to a defined length of 20 cm.

-   (C) The fiber bundle is transferred into the housing before the    melting process

The mini-module is put into a vacuum drying oven over night before thepotting process.

Example 9 Determining the Liquid Permeability (Lp) of a Membrane

The permeability was determined with either a hand bundle as describedin Example 8 or with flat sheet membranes. For determining the Lp of agiven hand bundle, said hand bundle is sealed at one end and a definedamount of water passes through the bundle under a certain pressure. Thisprocess will take a certain time. Based on said time, the membranesurface area, the pressure used and the volume of the water which haspassed the membrane, the Lp can be calculated. The equation used is

${Lp} = {\frac{V}{p \times A \times t} = \frac{V}{\pi \times d \times l \times n \times p \times t}}$

wherein Lp is the convective permeability [·10⁻⁴ cm/bar·s], V is thewater volume [cm³], p is the pressure [bar], t is the time, and A is theeffective membrane surface of the bundle with A=π·d·l·n. The pressureused was 400 mmHg. For determining the Lp of a flat sheet membrane, awater bath and test solution (water, dest.) is heated to 37° C. Themembrane (A=27.5 cm²) is soaked in the test solution for at least 30minutes. The soaked membrane is inserted into the measuring device. Amaximum pressure of 600 mmHg (0.8 bar) is applied. The time needed forthe passage of 1 ml water is determined. The equation used is

${Lp} = {\frac{{V({ml})} \times 750}{{A\left( {cm}^{2} \right)} \times {p({mmHg})} \times {t(s)}}.}$

1. A membrane for the removal of substances from a liquid, the membrane comprising at least one hydrophobic polymer selected from the group consisting of polysulfones, polyethersulfones, polyarylethersulfones, polyamides and polyacrylonitriles and at least one hydrophilic polymer, the membrane comprising 1-40 wt.-% of at least one of hydrophilic particles and hydrophobic particles, the particles having an average diameter of between 0.1 μm and 15 μm.
 2. The membrane according to claim 1, wherein the particles have an average diameter of between 0.1 μm and 10 μm.
 3. The membrane according to claim 1 wherein the hydrophobic particles are chosen from the group consisting of activated carbon, carbon nanotubes, hydrophobic silica, styrenic polymers, polydivinylbenzene polymers and styrene-divinylbenzene copolymers.
 4. The membrane according to claim 1, wherein the hydrophilic particles are anion or cation exchange particles.
 5. The membrane according to claim 4 wherein the anion exchange particles are based on polyquaternary ammonium functionalized styrene divinylbenzene copolymers.
 6. The membrane according to claim 5 wherein the anion exchange particles are based on polyquaternary ammonium functionalized vinylimidazolium methochloride vinylpyrrolidone copolymers.
 7. The membrane according to claim 5 wherein the polyquaternary ammonium copolymer is a copolymer of styrene and divinylbenzene with dimethyl(2-hydroxyethyl) ammonium and/or trimethylbenzyl ammonium functional groups.
 8. The membrane according to claim 1 wherein the membrane is one of a hollow fiber membrane and a flat sheet membrane.
 9. The membrane according to claim 1 wherein the wall thickness of the hollow fiber is below 150 μm.
 10. The membrane according to claim 1 wherein the particles are present in an amount of from 20 wt.-% to 35 wt.-% relative to the weight of the membrane.
 11. The membrane according to claim 1 wherein the membrane is at least one of a microporous membrane, a protein separation membrane and an ultrafiltration membrane.
 12. A method for preparing a hollow fiber membrane comprising at least one hydrophobic polymer selected from the group consisting of polysulfones, polyethersulfones, polyarylethersulfones, polyamides and polyacrylonitriles and at least one hydrophilic polymer, the membrane comprising 1-40 wt.-% of at least one of hydrophilic particles and hydrophobic particles, the particles having an average diameter of between 0.1 μm and 15 μm, the method comprising (a) grinding the particles to an average diameter of at least 15 μm in an aqueous solution; (b) combining the at least one hydrophilic and the at least one hydrophobic polymer with the suspension of (a); (c) stirring the polymer particle suspension to obtain a homogeneous polymer solution wherein the particles are suspended; (d) degassing the polymer particle suspension; (e) extruding the polymer particle suspension through an outer ring slit of a nozzle, wherein a center fluid is extruded through an inner opening of the nozzle; (f) immersing the precipitating fiber in a bath of non-solvent; (g) washing the membrane.
 13. A method for preparing a flat sheet membrane comprising at least one hydrophobic polymer selected from the group consisting of polysulfones, polyethersulfones, polyarylethersulfones, polyamides and polyacrylonitriles and at least one hydrophilic polymer, the membrane comprising 1-40 wt.-% of at least one of hydrophilic particles and hydrophobic particles, the particles having an average diameter of between 0.1 μm and 15 μm, the method comprising (a) grinding the particles to an average diameter of at least 15 μm in an aqueous solution; (b) combining the at least one hydrophilic and the at least one hydrophobic polymer with the suspension of (a); (c) stirring the polymer particle suspension to obtain a homogeneous polymer solution wherein the particles are suspended; (d) degassing the polymer particle suspension; (e) casting the polymer particle suspension as a uniform film onto a smooth surface; (f) washing the membrane.
 14. The method according to claim 12, wherein the water of (a) is the total amount of water which is needed for forming the final polymer solution.
 15. (canceled)
 16. A method for at least one of the adsorption of compounds, the isolation of compounds and the purification of a liquid, the method comprising preparing a hollow fiber membrane comprising at least one hydrophobic polymer selected from the group consisting of polysulfones, polyethersulfones, polyarylethersulfones, polyamides and polyacrylonitriles and at least one hydrophilic polymer, the membrane comprising 1-40 wt.-% of at least one of hydrophilic particles and hydrophobic particles, the particles having an average diameter of between 0.1 μm and 15 μm, and exposing the at least one of the compounds and the liquid to the membrane.
 17. The method of claim 16, wherein the compounds are selected from the group consisting of nucleic acids, unconjugated bilirubin, chenodeoxycholic acid, diazepam, cytokines and endotoxins.
 18. A device for at least one of the adsorption of compounds and purification of a liquid, the device comprising at least one of hollow fiber membranes and flat sheet membranes, the at least one of hollow fiber membranes and flat sheet membranes comprising at least one hydrophobic polymer selected from the group consisting of polysulfones, polyethersulfones, polyarylethersulfones, polyamides and polyacrylonitriles and at least one hydrophilic polymer, the at least one of hollow fiber membranes and flat sheet membranes comprising 1-40 wt.-% of at least one of hydrophilic particles and hydrophobic particles, the particles having an average diameter of between 0.1 μm and 15 μm.
 19. The membrane according to claim 2 wherein the hydrophobic particles are chosen from the group consisting of activated carbon, carbon nanotubes, hydrophobic silica, styrenic polymers, polydivinylbenzene polymers and styrene-divinylbenzene copolymers.
 20. The membrane according to claim 2 wherein the hydrophilic particles are anion or cation exchange particles.
 21. The membrane according to claim 19 wherein the hydrophilic particles are anion or cation exchange particles. 